Issue 26, 2024

Quantitative assessment of daratumumab in serum via intact light chain measurement using liquid chromatography-high resolution mass spectrometry: a method suitable for therapeutic drug monitoring

Abstract

Daratumumab, a pivotal treatment for multiple myeloma, exhibits considerable inter-patient variability in pharmacological clinical outcomes, likely attributed to serum concentration that may underscore the need for its therapeutic drug monitoring. This study aims to develop and validate a straightforward analytical method for quantifying daratumumab in serum, focusing on intact light chain determination, using liquid chromatography high-resolution mass spectrometry. The sample preparation involved immunoglobulin enrichment using Melon gel followed by a reduction step to dissociate the light from the heavy chains of immunoglobulins. The latter were then separated using a MabPac RP 2.1 × 50 mm chromatographic column and the intact light chains were detected and quantified using a Q Exactive Orbitrap mass spectrometer operating in ESI-positive ion mode at 17 500 resolution. The method demonstrated excellent linearity (R2 > 0.992) across a serum concentration range of 100 to 2000 μg mL−1 and good precision and accuracy: intra- and interday relative errors ranged from −5.1% to 6.5%, with a relative standard deviation of less than 5.8%. Clinical suitability was confirmed by analyzing 80 clinical samples from multiple myeloma patients treated with 1800 mg of daratumumab. 99% of the samples fell within the analytical range with a mean daratumumab concentration evaluated before the next administration (Ctrough) of 398 μg mL−1. These findings highlighted that intact light chain monoclonal antibody quantification could be a valid and robust alternative to either immunoassays or to LC-MS/MS targeting peptides for measuring daratumumab in clinical samples, positioning it as a suitable method for therapeutic drug monitoring applications.

Graphical abstract: Quantitative assessment of daratumumab in serum via intact light chain measurement using liquid chromatography-high resolution mass spectrometry: a method suitable for therapeutic drug monitoring

Supplementary files

Article information

Article type
Paper
Submitted
04 Mar 2024
Accepted
08 May 2024
First published
09 May 2024

Anal. Methods, 2024,16, 4240-4246

Quantitative assessment of daratumumab in serum via intact light chain measurement using liquid chromatography-high resolution mass spectrometry: a method suitable for therapeutic drug monitoring

G. Canil, G. Miolo, M. Simula, M. Rupolo, A. Steffan and G. Corona, Anal. Methods, 2024, 16, 4240 DOI: 10.1039/D4AY00404C

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